Research: The research is directed at generating animal models of human atherosclerosis by gene targeting and to use these animal models to study, at the molecular level, the role of increased secretion of apolipoprotein B-containing lipoproteins on atherogenesis. The secretion of apo B-containing lipoproteins is under the influence of apolipoprotein B (apo B) production, availability of lipoprotein building blocks, and the secretory rates. Elevated levels of plasma-apoB-containing lipoproteins are considered to be atherogenic in humans and mice. Specific aims 1 and 2 are to increase-plasma lipoprotein levels in mice by increasing the levels of apolipoprotein B (apoB) and microsomal triglyceride transfer protein (MTP) large subunit, respectively. This increased production will result from duplications of the normal genes at their natural loci by gene targeting and homologous recombination as described (Smithies and Kim, 1994). One advantage these mutants have over multiple-copy-random-integration transgenic models is the control of locus effects on gene expression. Finally, specific aim three is to create a polygenic mouse model with both duplications from specific aims l and 2. In addition, I will examine if the combination of each duplication with apoE deficiency increases atherosclerotic lesion severity. Environment: This institution is fully committed to the generation and use of animal models for human disease. Dr. Maeda and Dr. Smithies, a collaborator, are responsible for the generation of many mouse models. Dr. Maeda is one of the foremost researchers generating animal models of atherosclerosis by gene targeting. Her laboratory is located on the same floor as Dr. Smithies in the Department of Pathology. Trainees, students, and technicians from both laboratories share laboratory meetings and can readily exchange ideas and experimental experience.